title: Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome.
abstract: Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.
authors.affiliation: Department of Epigenetic Medicine, Faculty of Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Miyake
authors.forename: Chunshu
authors.initials: C
authors.lastname: Yang
authors.forename: Yohei
authors.initials: Y
authors.lastname: Minakuchi
authors.forename: Kenta
authors.initials: K
authors.lastname: Ohori
authors.forename: Masaki
authors.initials: M
authors.lastname: Soutome
authors.forename: Takae
authors.initials: T
authors.lastname: Hirasawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.forename: Noboru
authors.initials: N
authors.lastname: Adachi
authors.forename: Seiko
authors.initials: S
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Andoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurosawa
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005091:Exons; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D004247:DNA